(Gehirn & Geist / Spektrum.de, May 4, 2025)

Nils Althaus

How much people with chronic pain suffer has surprisingly little to do with the intensity of their pain. Researchers are learning to distinguish pain from suffering—and to target the latter directly.

Roughly one in five people in Germany lives with chronic pain. Their quality of life is often poor—sometimes comparable to that of cancer patients receiving palliative care. Ask these patients what is so terrible about their pain, and they might think you are making a cruel joke. But some researchers are asking the question in earnest. Their findings are casting pain in a new light—and could help relieve the suffering that accompanies it.

Doctors have known about pain asymbolia since the 1920s. People with the condition may remain remarkably unfazed by electric shocks or intense heat. Instead of crying out and pulling their arm away, they may smile or chat animatedly with researchers in the pain laboratory. Yet they can still distinguish painful stimuli from painless ones. They seem to feel pain without suffering from it. In nearly all documented cases, researchers have found lesions in the insula, a brain region hidden deep between the temporal, frontal and parietal lobes.

A similar resistance to suffering was often observed in patients whose cingulate cortex—then considered a possible emotional command center—was surgically severed to treat chronic pain in the 1950s and 1960s. These “cingulotomies” often failed to eliminate the pain, but patients no longer seemed to suffer from it. Ultramarathon runners, chili enthusiasts, and people with masochistic preferences likewise experience certain kinds of pain without finding them unpleasant.

Sascha Fink, a philosopher at the University of Erlangen, considers this distinction morally significant. “Pain that no one suffers from does not seem particularly important from a moral perspective. Suffering, by contrast, always matters because it is inseparable from negative experience.” Put differently: If the aim is to help people, the primary goal should be to reduce their suffering.

Unlike pain medicine, however, suffering medicine is not an established field. Tor Wager, a neuroscientist at Dartmouth College in New Hampshire, could help change that. His team investigates the neural foundations of mental states and has identified a number of “neural signatures”—patterns of brain activity calculated by computer models that can predict whether someone is experiencing fear, guilt, or pain. “We wanted to know whether there is a pattern that represents the subjective evaluation of all negative experiences—a kind of suffering network that becomes active whenever we find something unpleasant.”

To find out, the researchers exposed participants to four unpleasant stimuli at varying intensities: an unpleasant sound, a repulsive image, a hot probe placed against the skin, and a device that squeezed the thumb. The participants rated how negative they found each stimulus while their brain activity was recorded using functional magnetic resonance imaging (fMRI).

The Stronger the Signature, the More Negative the Experience

In the brain scans, Wager’s group found a pattern triggered by all four stimuli. The more strongly the signature appeared, the more negatively participants rated the experience. When something heightened their attention without producing negative feelings, however, the signature was absent.

“We were surprised to find anything like this,” Wager says. His model draws on signals from just over 50 brain regions. Six make the strongest statistical contributions, including the anterior midcingulate cortex (aMCC), the anterior insula, and the orbitofrontal cortex (OFC)—regions affected in pain asymbolia or cingulotomies. What would selectively activating these regions feel like? “Probably a sense that something is wrong and you need to get away—a kind of unease or fear,” Wager says.

The signature for general negative affect explained only about 30 percent of the participants’ ratings. Wager’s team therefore created an additional signature for each type of stimulus. Only by combining the general and stimulus-specific signatures could they predict 70 to 80 percent of the ratings.

The stimulus-specific signatures primarily involve sensory regions that receive information from the sense organs: the visual cortex for repulsive images, for example, and the auditory cortex for unpleasant sounds. Negative affect—which many scholars consider the core of suffering (see box)—therefore appears to be mediated by two neural systems: one general and another specific to each sensory modality. There may, in effect, be distinct forms of “heat suffering,” “sound suffering,” “pinching suffering,” and “image suffering.”

Whether these findings also apply to chronic pain remains uncertain. “You can’t switch chronic pain on and off,” Wager says. “That makes it much harder to distinguish its signals from other mental processes.”

Until recently, a widely accepted model of chronic pain centered on three anatomically distinct neural pathways. Two—the lateral and medial pathways—run from the body’s periphery through the spinal cord to different regions of the cerebral cortex. The third, known as the inhibitory pathway, travels in the opposite direction, from the brain down to the spinal cord. According to this model, the lateral pathway transmits the sensory dimensions of pain: where it is located in the body, how intense it is, and whether it feels throbbing, stabbing, or dull. It leads primarily to the somatosensory cortex.

The medial pathway, by contrast, is responsible for the affective and motivational dimensions: How bad is it, and how strongly do I want to avoid it? This “suffering pathway” terminates in the aMCC and anterior insula—regions that Wager’s research implicates in general negative affect.

Such a clean separation between pain and suffering would be convenient for researchers, but the picture has become increasingly complicated. “We now know that our earlier thinking was too simplistic,” says Prasad Shirvalkar, a pain researcher at the University of California, San Francisco. “In some participants, stimulating the aMCC reduces tingling in the arm—which is a sensory signal, not an affective one. Pain-related information also reaches the brain through other pathways.”

Shirvalkar’s group specializes in deep-brain stimulation, in which magnetic or electrical fields are used to activate or inhibit brain regions. In patients with exceptionally persistent chronic pain, electrodes are implanted directly into the brain. The latest generation of electrodes can both alter neural activity and record it over extended periods. This means researchers do not have to induce pain at a specific moment; they can simply wait for it to occur. Patients complete questionnaires several times a day, and their answers are compared with the signals recorded by the electrodes. Like Wager’s group, Shirvalkar’s team uses classification algorithms to search for patterns of brain activity associated with pain ratings.

Two years ago, his team succeeded. For the first time, researchers were able to predict the intensity of chronic pain in four patients using data recorded directly from their brains. But they had to create a separate classification model for each patient. “We wanted to find a general signature, but the differences between individual brains were too large,” Shirvalkar explains.

His model cannot be directly compared with Wager’s. It does not predict a continuous measure of negativity, only whether a person is currently experiencing a high or low level of pain. The researchers were also limited to measuring activity in the locations where electrodes had been implanted. Nevertheless, they found that the OFC was probably more important than the aMCC for predicting patients’ ratings of chronic pain. When the same patients were subjected to acute pain, the relationship was reversed: Signals from the aMCC were better predictors.

Acute and Chronic Pain Differ in Many Ways

Shirvalkar’s findings confirmed what other studies had already suggested: Acute and chronic pain differ in many respects. “I would be surprised if we found a single neural signature for every form of pain,” Wager says. “Musculoskeletal disorders, irritable bowel syndrome, arthritis, and migraine are simply too heterogeneous.”

“Neural pain patterns are complex, but activity in many brain regions is correlated,” Shirvalkar adds. “Usually, six or seven nonoverlapping networks are enough to identify chronic pain.” His experiments, which have not yet been published, offer a glimpse of what personalized medicine may eventually be able to achieve.

Each of Shirvalkar’s severely affected participants had 10 to 12 arrays implanted, with 16 electrodes in each array. For 10 days, the participants completed pain questionnaires while the electrodes continuously recorded their brain activity. Computers used the data to build a separate classification model for each person. According to Shirvalkar, these models can predict the participants’ pain ratings with considerable precision. The long-term goal is to develop a closed-loop system: When the calculated pain rating crosses a certain threshold, the electrodes would automatically switch from recording to stimulation, altering the activity of brain regions to reduce the patient’s pain or suffering without requiring any action from the patient.

New approaches to pain treatment are urgently needed. Many treatments—whether manual therapy, surgery, or medication—have relatively limited effectiveness. Even the strongest painkillers, opioids, become less effective the longer they are used. They also cause side effects and can lead to dependence.

When people with chronic pain are asked what causes them the most suffering, high pain intensity is often only one of many answers. In a 2008 study led by Dennis Turk, nearly 1,000 participants were asked which aspects of their lives a pain treatment would need to improve for them to consider it effective. Of 19 possible outcomes, the two they valued most were “being able to enjoy life” and “feeling less tired,” closely followed by “emotional well-being” and “physical activities.”

“For many people, suffering is defined not by pain intensity alone but by other variables,” says Winfried Rief, a professor of clinical psychology and psychotherapy at the University of Marburg. Psychotherapy is therefore increasingly adopting approaches that aim primarily to reduce suffering rather than pain itself. “We might ask patients what they would like their gravestone to say: He spent his whole life fighting pain or He was a wonderful grandfather to his grandchildren. Questions like this can often reduce the subjective importance of pain.”

Therapists also draw on techniques used to treat anxiety. People with phobias are gradually exposed to the object of their fear, such as a spider or a high bridge. This kind of exposure can also help with pain. “Many people with chronic pain are still given advice that is actually harmful: Rest, and avoid painful movements! That can help turn pain into a chronic condition.” Instead, patients are encouraged to move even if doing so causes mild pain. “In practice, we actively work our way toward the pain. What happens if I lift an empty crate? What if it contains a few bottles? Patients often realize that they are capable of more than they thought and begin to escape the cycle of pain and fear.” The pain remains, but gradually loses its power to frighten them.

Targeting subjective suffering also makes sense because suffering can itself cause pain. The reverse relationship is more familiar: Chronic pain produces suffering, including anxiety and depression. Less widely understood is that anxiety and depression can themselves contribute to chronic pain. “People with depression perceive pain differently. They tolerate it less well and make more pessimistic predictions. The relevant neural networks overlap, which is why some antidepressants also relieve pain,” Rief explains.

Pain Reprocessing Therapy makes use of this insight. It combines elements of exposure therapy with other forms of cognitive behavioral therapy. A central feature is that patients are told at the outset—sometimes with the help of brain-imaging data—that their pain is not caused by physical damage. Instead, the brain is mistakenly interpreting messages from the body as dangerous.

In a study led by Yoni Ashar and Tor Wager, two-thirds of patients were almost pain-free after eight weeks of treatment. “The patients learned not to suffer as much from the pain they were already experiencing. And as the suffering decreased, the pain diminished as well.” Functional magnetic resonance imaging again showed decreased activity in the aMCC and anterior insula. “These regions seem to connect pain with feelings of suffering and urgency,” Wager says.

Smadar Bustan, a philosopher and clinical researcher, argues that pain-related suffering should be introduced as an independent outcome measure. Pain is generally assessed along two dimensions: intensity and “unpleasantness.” But according to Bustan, these terms do not capture every relevant experience. “The sense of going through something unbearable—the feeling of being overwhelmed and the despair that accompany some experiences of pain—cannot simply be described as intense or unpleasant. They belong to a third category: suffering.” This may explain why patients sometimes report pain intensities that exceed the scale they have been given—rating their pain a 12, for example, when the scale only runs from one to 10.

A Sense of Control Relieves Pain

Bustan and her colleagues conducted several studies on pain and the suffering associated with it. In one study led by Martin Löffler, participants could stop a painful stimulus as soon as they found it unbearable. When a computer program rather than the participants determined when the stimulus would end, participants experienced much greater suffering—even when the computer selected exactly the same duration. Having control over pain can therefore alter suffering without necessarily changing the pain’s intensity or unpleasantness. Although the study was small and requires further confirmation, it could help explain the seemingly paradoxical behavior of ultramarathon runners and masochists: Their pain, and its duration, is self-chosen. Consistent with this explanation, painful stimuli produce less activity in the insula and surrounding brain regions in masochists when the stimulus is paired with an image from a masochistic context.

Taken together, findings from these different disciplines show that suffering caused by chronic pain takes place in the brain—and can be treated there. Fortunately, destroying brain tissue, as in a cingulotomy, is rarely necessary. Clinicians have increasingly precise tools for brain stimulation and therapy at their disposal. That offers hope to people who do not merely experience pain but suffer from it.

What Is Suffering?

In the 1980s, the American physician Eric Cassell argued that medicine should primarily treat suffering rather than disease. He defined suffering as “the state of severe distress associated with events that threaten the intactness of the person.” This definition remains widely used in medicine, but critics have called it circular because “severe distress” can hardly be explained without invoking suffering.

Researchers have therefore proposed alternatives, including “negative affect,” “impaired agency,” and an “urge to change the situation.” In a 2020 collection, philosophers Jennifer Corns, Michael Brady, and David Bain argue that negative affect—the experience of unpleasantness—is probably the most fundamental element of suffering.

If negative affect is treated as the sole criterion for suffering, however, the patient’s own wishes can be disregarded. Suppose someone asks to have the dose of a sedating painkiller reduced so that they can remain mentally present. Their negative affect increases because their pain becomes more intense. Yet it seems paradoxical to claim that they are suffering more when they have chosen greater pain over mental clouding themselves.

Brady has proposed an account that avoids this objection. On his view, suffering contains two elements: negative affect and the desire to avoid it. For the patient in the given example, the desire to avoid negative affect is evidently weaker than the desire to remain mentally present. Brady’s theory can therefore explain why the patient would suffer more if the medication were kept at the higher dose: Doing so would frustrate the stronger desire for mental presence.

References

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